Novel method for preparing 5-deoxytriacetyl ribose

Abstract

The invention discloses a novel method for preparing 5-deoxytriacetyl ribose, belongs to the technical field of drug synthesis, and aims to solve the problems that the existing method for preparing 5-deoxytriacetyl ribose is totally divided into five steps, and D-ribose is used as an initial raw material, so that more reaction steps are needed, longer reaction time is needed, the production cost is high, and industrial production is difficult to implement. Tetraacetyl ribose RIB-0 is taken as an initial raw material, the tetraacetyl ribose RIB-0 is taken as a common compound and is relatively easy to obtain, the production cost is reduced, the 5-deoxytriacetyl ribose can be industrially produced, the original five steps for preparing the 5-deoxytriacetyl ribose are simplified into four steps, the reaction steps are relatively simple, the reaction time is shortened, and the yield of the 5-deoxytriacetyl ribose is improved. The yield is improved, and the purity of the finally prepared target compound is greater than 99%.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a new method for preparing 5-deoxytriacetylribose. Background Art

[0002] 5-Deoxytriacetylribose is a key intermediate of the anti-tumor drug capecitabine. The preparation method of 5-deoxytriribose has been reported in literature and patents. Generally, D-ribose is used as the starting material, and the target product is obtained through a total of five steps of methanol acetone protection, toluene sulfonylation protection, reduction, deprotection and acetylation.

[0003] After searching, a document entitled "An efficient convergent synthesizes is of adenosine-5'-Na lkyluuronamides" in the ELSEVI ER database disclosed the preparation steps of 5-deoxytriacetylribose.

[0004] According to reports in journals and patent literature, the known method for synthesizing 5-deoxy-D-ribose is described in Journal of Organism Chemistry 43 (1), 161, 1978, Carbohydrate Research 338 (4), 303, 2003 and Nutrition Medicine and Biol 31 (8), 1033, 2004. D-ribose is used as a starting material. In a methanol solvent, D-ribose is first catalyzed by acidification to generate a methylated product 1-0-methyl-D-ribose at the 1-position. The methylated product is then reacted with acetone and 2,2-dimethoxypropane without separation to obtain a forked intermediate 2,3-O-isopropylidene-1-O-methyl-D-ribose. The product is then esterified with methanesulfonyl chloride in pyridine to obtain 1-methyl-2,3-O-isopropylidene-5-methylsulfonyl-D-ribose. The latter is then reacted with DMSO as a solvent by borohydration. The method comprises the following steps: reducing the 5-deoxy intermediate with sodium chloride to obtain a 5-deoxy intermediate, performing 1-position demethylation, 2-position deisopropylidene protection, and 1,2,3-acetylation with acetic anhydride in an acetic acid aqueous solution to obtain the desired intermediate. The existing method for preparing 5-deoxytriacetylribose uses D-ribose as a starting material, and is divided into five steps in total, namely, methanol acetone protection, p-toluenesulfonyl protection, reduction, deprotection, and acetylation. Using D-ribose as a starting material has many reaction steps and requires a long reaction time, resulting in high production costs and difficulty in implementing industrial production.

[0005] To solve the above problems, a new method for preparing 5-deoxytriacetyl ribose is proposed. Summary of the invention

[0006] The object of the present invention is to provide a new method for preparing 5-deoxytriacetyl ribose, which solves the problem that the existing method for preparing 5-deoxytriacetyl ribose in the background art is divided into five steps in total, uses D-ribose as a starting material, has many reaction steps, requires a long reaction time, leads to high production cost, and is difficult to implement industrial production.

[0007] To achieve the above object, the present invention provides the following technical solution: a new method for preparing 5-deoxytriacetyl ribose, comprising four reaction steps:

[0008] S1: Preparation of RI B: Using tetraacetyl ribose RI B-0 as the starting material, RI B was obtained by selective deacetylation;

[0009] S2: Preparation of Ts-ACF: Acylation of RIB to obtain Ts-ACF;

[0010] S3: Preparation of Br-ACF: Bromination of Ts-ACF to obtain Br-ACF;

[0011] S4: ACF preparation: ACF is prepared by hydrogenation reduction of Br-ACF.

[0012] Further, the RIB preparation comprises the following steps:

[0013] S11: Preparation and insulation: In a 1L three-necked flask, keep the preparation temperature between 20-25°C, add L-1754 lipase, PBS, and then add THF solution of RI B-0, keep warm for 19 hours, and there is no raw material left on the plate;

[0014] S12: RI B extraction: DCM was added, the phases were separated, the lower white turbid organic phase was taken, celite was added, the phases were filtered, and the phases were separated again. The dichloromethane phase was concentrated to dryness to obtain a yellow viscous substance RI B.

[0015] Furthermore, the configuration process of the PBS is as follows:

[0016] S111: PBS preparation: Dissolve sodium dihydrogen phosphate monohydrate in pure water, then add sodium hydroxide to adjust the pH to 7, then add pure water and leave at room temperature.

[0017] Furthermore, the Ts-ACF preparation comprises the following steps:

[0018] S21: cooling: adding RIB and chloroform, and then adding quaternary ammonium salt, preferably triethylbenzylammonium chloride TEBA, and cooling to 10°C;

[0019] S22: Confirm the completion of the reaction: control the temperature at 0-10°C, add p-toluenesulfonyl chloride dropwise, add it within 10 minutes, keep the temperature at 0-10°C for 4 hours, and confirm the completion of the reaction by tapping the plate;

[0020] S23: Acylation catalysis: Wash with water, separate the phases, and spin-dry the organic phase to obtain a yellow oil Ts-ACF. This toluene acylation reaction uses toluene-water two-phase phase transfer catalysis with a quaternary ammonium salt as a catalyst.

[0021] Furthermore, the Br-ACF preparation comprises the following steps:

[0022] S31: Reactor configuration: Ts-ACF, dimethylacetamide DMAC and alkali metal bromide are added to the reactor in sequence, alkali metal bromide is used as the bromination reagent, preferably sodium bromide, and the reaction is carried out at 50-55°C for 3 hours, and the plate is pressed to confirm the end of the reaction;

[0023] S32: dissolving and filtering: adding toluene solvent to dissolve, the by-product sodium p-toluenesulfonate precipitates, and then filtering;

[0024] S33: separation and extraction: washing with water, separating the phases, taking the organic phase, and spinning the toluene phase to obtain a Br-ACF concentrate.

[0025] Furthermore, the ACF preparation comprises the following steps:

[0026] S41: Configuration analysis: Br-ACF concentrate, triethylamine, RaneyNi and reaction solvent are added to the reactor, methanol aqueous solution is used as the reaction solvent, preferably the methanol concentration is 70%-80%, hydrogen is introduced, the reaction is carried out at 50°C, and sampling is performed by TLC analysis;

[0027] S42: Concentration under reduced pressure and extraction: After the reaction is completed, methanol is evaporated under reduced pressure, toluene is added for extraction, the phases are separated, acetic acid is added to the organic phase for washing until the pH is less than 7, the phases are separated, the organic phase is concentrated under reduced pressure, isopropanol is added for crystallization, and ACF is obtained.

[0028] Furthermore, the TLC analysis, i.e. thin layer chromatography analysis, is used to separate different compounds and confirm the structure of the compound after the reaction is completed, so as to facilitate the subsequent vacuum extraction and purification of the target compound.

[0029] The reaction scheme of the present invention is as follows:

[0030]

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The present invention provides a new method for preparing 5-deoxytriacetyl ribose, which uses tetraacetyl ribose RI B-0 as a starting material. Tetraacetyl ribose RI B-0 is a common compound that is relatively easy to obtain, which reduces the production cost, so that 5-deoxytriacetyl ribose can be industrially produced, thereby solving the problem that the existing method for preparing 5-deoxytriacetyl ribose has high production cost and is difficult to implement industrial production.

[0033] 2. The present invention provides a new method for preparing 5-deoxytriacetyl ribose, which simplifies the original five steps for preparing 5-deoxytriacetyl ribose into four steps, and the reaction steps are relatively simple, which reduces the reaction time and is conducive to improving the yield. The purity of the target compound finally produced is greater than 99%, which solves the problem that the existing method for preparing 5-deoxytriacetyl ribose is divided into five steps in total, uses D-ribose as a starting material, has more reaction steps, and requires a long reaction time. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a schematic diagram of the reaction route of the present invention;

[0035] Figure 2 It is a schematic diagram of the reaction process of the present invention;

[0036] Figure 3 It is a specific structural schematic diagram of the reaction process of the present invention. DETAILED DESCRIPTION

[0037] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] In order to solve the technical problems that the existing method for preparing 5-deoxytriacetylribose is divided into five steps, using D-ribose as the starting material has many reaction steps and requires a long reaction time, resulting in high production costs and difficulty in implementing industrial production, such as Figure 1-Figure 3 As shown, the following preferred technical solutions are provided:

[0039] A new method for preparing 5-deoxytriacetylribose comprises the following four reaction steps:

[0040] Step 1: Preparation of RIB: Using tetraacetyl ribose RIB-0 as the starting material, RIB is prepared by selective deacetylation;

[0041] Step 2: Preparation of Ts-ACF: Acylation of RI B to obtain Ts-ACF;

[0042] Step 3: Preparation of Br-ACF: Bromination of Ts-ACF to obtain Br-ACF;

[0043] Step 4: ACF preparation: ACF is prepared by hydrogenation reduction of Br-ACF.

[0044] The present invention will be further described below in conjunction with the embodiments.

[0045] Embodiment 1:

[0046] The method for preparing RI B in this embodiment comprises the following steps:

[0047] Step 1: Preparation and insulation: Keep the preparation temperature between 20-25°C, add 9.0g L-1754 lipase and 424.2ml PBS, stir at room temperature for 20min, add 6.0g RI B-0 THF solution at 20-25°C, the THF solution is prepared by 6.0g RI B-0 and 47.4ml THF, and then keep warm at 20-25°C for 19h, there is no raw material left on the plate, PE:EA=1:1, phosphomolybdic acid color development;

[0048] Step 2: RIB extraction: add 500 ml DCM, separate the phases, take the lower white turbid organic phase, add 1% diatomaceous earth, stir for 30 min, filter, separate the phases again, and concentrate the dichloromethane phase to dryness (-0.095 MPa, ≤50° C.) to obtain 3.0 g of yellow viscous RIB, with a yield of 87.7%.

[0049] Table 1 shows the RIB and its yield obtained under different extraction temperature and different ratios of extraction raw materials and DCM.

[0050]

[0051]

[0052] Embodiment 2:

[0053] The configuration process of PBS in this embodiment is as follows:

[0054] Preparation of PBS: Dissolve 20.7 g of sodium dihydrogen phosphate monohydrate in 1.2 L of pure water, stir for 10 min, then add 100 ml of 1 M sodium hydroxide to adjust the pH to 7, then add 200 ml of pure water, stir for 30 min, and leave at room temperature.

[0055] Embodiment three:

[0056] The method for preparing Ts-ACF in this embodiment has the following steps:

[0057] Step 1: Cooling: Add 2.40 g RI B, 6 ml chloroform, and 1.05 g quaternary ammonium salt, preferably triethylbenzylammonium chloride TEBA, into a 50 ml three-necked flask, and cool to 10°C;

[0058] Step 2: Confirm the completion of the reaction: add p-toluenesulfonyl chloride dropwise at 0-10°C for 10 minutes, keep at 0-10°C for 4 hours, spot the plate to confirm the completion of the reaction, PE:EA=1:1, phosphomolybdic acid color development;

[0059] Step 3: Acylation catalysis: add 12 ml*2 water to wash, separate the phases, and spin-dry the organic phase to obtain 3.43 g of yellow oil Ts-ACF with a yield of 92%. This toluene acylation reaction adopts toluene-water two-phase phase transfer catalysis with quaternary ammonium salt as catalyst.

[0060] Embodiment 4:

[0061] The method for preparing Br-ACF in this embodiment comprises the following steps:

[0062] Step 1: Reactor configuration: 30 g Ts-ACF, 150 ml dimethylacetamide DMAC and 12 g alkali metal bromide are added to the reactor in sequence, alkali metal bromide is used as the bromination reagent, preferably sodium bromide, and the reaction is carried out at 50-55°C for 3 hours. The reaction is confirmed to be complete by tapping the plate. Dimethylformamide or dimethylacetamide DMAC is used as the solvent, preferably dimethylacetamide DMAC;

[0063] Step 2: Dissolution and filtration: Add 5 ml of toluene solvent to dissolve, let the by-product sodium p-toluenesulfonate precipitate and then filter;

[0064] Step 3: Separation and extraction: Wash with 5 ml*2 water, separate the phases, take the organic phase, spin-dry the toluene phase to obtain Br-ACF concentrate.

[0065] Embodiment five:

[0066] The method for preparing ACF in this embodiment comprises the following steps:

[0067] Step 1: Configuration analysis: Br-ACF concentrate, 40 g triethylamine, 0.5 g Raney Ni and 100 ml reaction solvent are added to the reactor, methanol aqueous solution is used as the reaction solvent, preferably the methanol concentration is 70%-80%, 1 MPa hydrogen is introduced, the reaction is carried out at 50°C, and sampling is performed by TLC analysis;

[0068] Step 2: Extraction under reduced pressure: After the reaction is completed, methanol is evaporated under reduced pressure, 200 mL of toluene is added for extraction, the phases are separated, 5% acetic acid is added to the organic phase to wash until the pH is <7, the phases are separated, the organic phase is concentrated under reduced pressure, 60 mL of isopropanol is added for crystallization, and ACF18 g is obtained with HPLC purity ≥99%.

[0069] Table 2 shows the extraction results obtained by configuration analysis at different temperatures

[0070]

[0071]

[0072] Embodiment six:

[0073] The TLC analysis in this example is thin layer chromatography analysis, which is a commonly used method for separating and analyzing compounds. TLC analysis can separate different compounds, thereby further confirming the compound structure after the reaction is completed, so as to facilitate subsequent vacuum extraction and purification of the target compound.

[0074] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0075] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A new method for preparing 5-deoxytriacetylribose, It is characterized in that The reaction equation is as follows: The process includes the following four reaction steps: S1: RIB preparation: RIB was prepared by selective deacetylation of tetraacetyl ribose RIB-0 as the starting material; S2: Preparation of Ts-ACF: Acylation of RIB to obtain Ts-ACF; S3: Preparation of Br-ACF: Bromination of Ts-ACF to obtain Br-ACF; S4: ACF preparation: ACF is prepared by hydrogenation reduction of Br-ACF.

2. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 1, Features: The RIB preparation comprises the following steps: S11: Preparation and insulation: In a 1L three-necked flask, keep the preparation temperature between 20-25°C, add L-1754 lipase, PBS, and then add THF solution of RIB-0, keep warm for 19 hours, and there is no raw material left on the plate; S12: RIB extraction: DCM was added, the phases were separated, the lower white turbid organic phase was taken, celite was added, the phases were filtered, the phases were separated again, and the dichloromethane phase was concentrated to dryness to obtain a yellow viscous substance RIB.

3. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 2, Features: The configuration process of the PBS is as follows: S111: PBS preparation: Dissolve sodium dihydrogen phosphate monohydrate in pure water, then add sodium hydroxide to adjust the pH to 7, then add pure water and leave at room temperature.

4. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 2, Features: The Ts-ACF preparation comprises the following steps: S21: cooling: adding RIB and chloroform, and then adding quaternary ammonium salt, preferably triethylbenzylammonium chloride TEBA, and cooling to 10°C; S22: Confirm the completion of the reaction: control the temperature at 0-10°C, add p-toluenesulfonyl chloride dropwise, add it within 10 minutes, keep the temperature at 0-10°C for 4 hours, and confirm the completion of the reaction by tapping the plate; S23: Acylation catalysis: Wash with water, separate the phases, and spin-dry the organic phase to obtain a yellow oily substance Ts-ACF.

5. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 4, Features: The p-toluene acylation reaction adopts toluene-water two-phase phase transfer catalysis and uses quaternary ammonium salt as catalyst.

6. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 1, Features: The Br-ACF preparation comprises the following steps: S31: Reactor configuration: Ts-ACF, dimethylacetamide DMAC and alkali metal bromide are added to the reactor in sequence, and the reaction is carried out at 50-55°C for 3 hours, and the plate is pressed to confirm the completion of the reaction; S32: dissolving and filtering: adding toluene solvent to dissolve, the by-product sodium p-toluenesulfonate precipitates, and then filtering; S33: separation and extraction: washing with water, separating the phases, taking the organic phase, and spinning the toluene phase to obtain a Br-ACF concentrate.

7. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 6, Features: The alkali metal bromide used as the bromination agent is preferably sodium bromide.

8. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 1, Features: The ACF preparation comprises the following steps: S41: Configuration analysis: Br-ACF concentrate, triethylamine, RaneyNi and reaction solvent were added to the reactor, and then hydrogen was introduced. The reaction was carried out at 50°C, and samples were taken for TLC analysis; S42: Evaporation under reduced pressure and extraction: After the reaction is completed, methanol is evaporated under reduced pressure, toluene is added for extraction, the phases are separated, acetic acid is added to the organic phase for washing until pH < 7, the phases are separated, the organic phase is concentrated under reduced pressure, isopropanol is added for crystallization, and ACF is obtained.

9. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 8, Features: The reaction solvent during the configuration analysis is a methanol aqueous solution, and the methanol concentration is preferably 70%-80%.

10. A novel method for preparing 5-deoxytriacetylribose as claimed in claim 8, Features: The TLC analysis is thin layer chromatography analysis, which is used to separate different compounds and confirm the structure of the compound after the reaction is completed, so as to facilitate the subsequent reduced pressure evaporation and extraction to purify the target compound.

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